Potassium Hydroxide → 3-tert-butoxycarbonyl-7-chloro-6-(2-isopropoxy-ethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine

HRID 2041347Notes

Reaction equation

HRID 2041347 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20]C(=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CCC2C(SC(=O)N(C)C)=C(Cl)C=C(Cl)C=2CC1)=O)(C)(C)C.[OH-].[K+].I[CH2:55][CH2:56][O:57][CH:58]([CH3:60])[CH3:59]>CO.[Cl-].[NH4+]>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:55][CH2:56][O:57][CH:58]([CH3:60])[CH3:59])=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]

Participants

7

Reactant 4

HCID 14797Potassium HydroxideHCID 186691542-(2-Iodoethoxy)propaneHCID 576559793-tert-butoxycarbonyl-7-chloro-6-dimethylaminocarbonylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineHCID 576562773-tert-butoxycarbonyl-7,9-dichloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine

Product 1

HCID 667068993-tert-butoxycarbonyl-7-chloro-6-(2-isopropoxy-ethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineYield 63%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 25517Ammonium ChlorideSolvent2×

Conditions

Temperature
57.5 °C

Procedure

To a 4:1 mixture of 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 3-tert-butoxycarbonyl-7,9-dichloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (200 mg, 0.52 mmol) in methanol (5 mL) under nitrogen, add potassium hydroxide (0.9 g, 16.1 mmol) at ambient temperature. When the mixture becomes homogenous, heat at 55-60° C. for 2-3 h, until TLC shows the disappearance of starting material. Cool to ambient temperature, add aqueous saturated ammonium chloride, extract three times with diethyl ether, dry over anhydrous MgSO4, and concentrate in vacuo. Dissolve the crude 3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine in anhydrous THF (5 mL) under nitrogen and add with stirring 1.0 M potassium t-butoxide in THF (1.0 mL) at ambient temperature. After 10 min, add 2-(2-iodoethoxy)propane (223 mg, 1.04 mmol), and allow the reaction to continue overnight. Dilute with aqueous saturated ammonium chloride, extract the mixture three times with diethyl ether, dry over anhydrous MgSO4, and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (12:1) to provide 3-tert-butoxycarbonyl-7-chloro-6-(2-isopropoxy-ethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a clear oil (127 mg, 63%). Use a method similar to the General Procedure 1-4 to give the title compound as a white solid. MS (ES+) m/z: 300 (M+H)+.

Workup

  1. temperatureCool to ambient temperature
  2. extractionextract three times with diethyl ether
  3. dry with materialdry over anhydrous MgSO4
  4. concentrationconcentrate in vacuo
  5. dissolutionDissolve the crude 3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine in anhydrous THF (5 mL) under nitrogen
  6. additionadd
  7. customthe reaction
  8. waitto continue overnight
  9. extractionextract the mixture three times with diethyl ether
  10. dry with materialdry over anhydrous MgSO4
  11. concentrationconcentrate in vacuo
  12. customPurify by chromatography on silica gel eluting with hexane/EtOAc (12:1)

Sources & evidence

ORD record
ord-f6b8b13b05ce410691f9d77af0759be8
Source dataset
uspto-grants-2013_11
Patent number
US08580780B2

Reaction notes

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